Publications by authors named "Jeffrey Krischer"

241 Publications

Associations of breastfeeding with childhood autoimmunity, allergies, and overweight: The Environmental Determinants of Diabetes in the Young (TEDDY) study.

Am J Clin Nutr 2021 Apr 8. Epub 2021 Apr 8.

Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany; and Forschergruppe Diabetes, Technical University Munich, at Klinikum rechts der Isar, Munich, and Forschergruppe Diabetes eV, Neuherberg, Germany.

Background: Breastfeeding has beneficial effects on numerous health outcomes.

Objectives: We investigated whether breastfeeding duration is associated with the development of early childhood autoimmunity, allergies, or obesity in a multinational prospective birth cohort.

Methods: Infants with genetic susceptibility for type 1 diabetes (n = 8676) were followed for the development of autoantibodies to islet autoantigens or transglutaminase, allergies, and for anthropometric measurements to a median age of 8.3 y (IQR: 2.8-10.2 y). Information on breastfeeding was collected at 3 mo of age and prospectively thereafter. A propensity score for longer breastfeeding was calculated from the variables that were likely to influence any or exclusive breastfeeding. The risks of developing autoimmunity or allergy were assessed using Cox proportional hazards models, and the risk of obesity at 5.5 y of age was assessed using logistic regression with adjustment by the propensity score.

Results: Breastfeeding duration was not associated with a lower risk of either islet or transglutaminase autoimmunity (any breastfeeding >6 mo, adjusted HR: 1.07; 95% CI: 0.96, 1.19; exclusive breastfeeding >3 mo, adjusted HR: 1.03; 95% CI: 0.92, 1.15). Exclusive breastfeeding >3 mo was associated with a decreased risk of seasonal allergic rhinitis (adjusted HR: 0.70; 95% CI: 0.53, 0.92; P < 0.01). Any breastfeeding >6 mo and exclusive breastfeeding >3 mo were associated with decreased risk of obesity (adjusted OR: 0.62; 95% CI: 0.47, 0.81; P < 0.001; and adjusted OR: 0.68; 95% CI: 0.47, 0.95; P < 0.05, respectively).

Conclusions: Longer breastfeeding was not associated with a lower risk of childhood (islet or transglutaminase) autoimmunity in genetically at-risk children but was associated with decreased risk of seasonal allergic rhinitis and obesity at 5.5 y of age.
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http://dx.doi.org/10.1093/ajcn/nqab065DOI Listing
April 2021

Transcriptional networks in at-risk individuals identify signatures of type 1 diabetes progression.

Sci Transl Med 2021 Mar;13(587)

Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge CB2 0AW, UK.

Type 1 diabetes (T1D) is a disease of insulin deficiency that results from autoimmune destruction of pancreatic islet β cells. The exact cause of T1D remains unknown, although asymptomatic islet autoimmunity lasting from weeks to years before diagnosis raises the possibility of intervention before the onset of clinical disease. The number, type, and titer of islet autoantibodies are associated with long-term disease risk but do not cause disease, and robust early predictors of individual progression to T1D onset remain elusive. The Environmental Determinants of Diabetes in the Young (TEDDY) consortium is a prospective cohort study aiming to determine genetic and environmental interactions causing T1D. Here, we analyzed longitudinal blood transcriptomes of 2013 samples from 400 individuals in the TEDDY study before both T1D and islet autoimmunity. We identified and interpreted age-associated gene expression changes in healthy infancy and age-independent changes tracking with progression to both T1D and islet autoimmunity, beginning before other evidence of islet autoimmunity was present. We combined multivariate longitudinal data in a Bayesian joint model to predict individual risk of T1D onset and validated the association of a natural killer cell signature with progression and the model's predictive performance on an additional 356 samples from 56 individuals in the independent Type 1 Diabetes Prediction and Prevention study. Together, our results indicate that T1D is characterized by early and longitudinal changes in gene expression, informing the immunopathology of disease progression and facilitating prediction of its course.
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http://dx.doi.org/10.1126/scitranslmed.abd5666DOI Listing
March 2021

Maternal food consumption during late pregnancy and offspring risk of islet autoimmunity and type 1 diabetes.

Diabetologia 2021 Mar 30. Epub 2021 Mar 30.

Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA.

Aims/hypothesis: We aimed to investigate the association between maternal consumption of gluten-containing foods and other selected foods during late pregnancy and offspring risk of islet autoimmunity (IA) and type 1 diabetes in The Environmental Determinants of Diabetes in the Young (TEDDY) study.

Methods: The TEDDY study recruited children at high genetic risk for type 1 diabetes at birth, and prospectively follows them for the development of IA and type 1 diabetes (n = 8556). A questionnaire on the mother's diet in late pregnancy was completed by 3-4 months postpartum. The maternal daily intake was estimated from a food frequency questionnaire for eight food groups: gluten-containing foods, non-gluten cereals, fresh milk, sour milk, cheese products, soy products, lean/medium-fat fish and fatty fish. For each food, we described the distribution of maternal intake among the four participating countries in the TEDDY study and tested the association of tertile of maternal food consumption with risk of IA and type 1 diabetes using forward selection time-to-event Cox regression.

Results: By 28 February 2019, 791 cases of IA and 328 cases of type 1 diabetes developed in TEDDY. There was no association between maternal late-pregnancy consumption of gluten-containing foods or any of the other selected foods and risk of IA, type 1 diabetes, insulin autoantibody-first IA or GAD autoantibody-first IA (all p ≥ 0.01). Maternal gluten-containing food consumption in late pregnancy was higher in Sweden (242 g/day), Germany (247 g/day) and Finland (221 g/day) than in the USA (199 g/day) (pairwise p < 0.05).

Conclusions/interpretation: Maternal food consumption during late pregnancy was not associated with offspring risk for IA or type 1 diabetes.

Trial Registration: ClinicalTrials.gov NCT00279318.
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http://dx.doi.org/10.1007/s00125-021-05446-yDOI Listing
March 2021

Pregnancy in women with osteogenesis imperfecta: Pregnancy characteristics, maternal, and neonatal outcomes.

Am J Obstet Gynecol MFM 2021 Mar 26:100362. Epub 2021 Mar 26.

Departments of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles (UCLA) Los Angeles, California; Departments of Human Genetics, David Geffen School of Medicine at University of California at Los Angeles (UCLA) Los Angeles, California; Departments of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles (UCLA) Los Angeles, California; Departments of Pediatrics, David Geffen School of Medicine at University of California at Los Angeles (UCLA) Los Angeles, California. Electronic address:

Background: Women with rare diseases such as osteogenesis imperfecta may consider pregnancy, although data regarding outcomes, specific risks, and management strategies is lacking.

Objective: The Brittle Bone Disorders Consortium of the National Institute of Health Rare Diseases Clinical Research Network established an Osteogenesis Imperfecta Pregnancy Registry to collect and evaluate pregnancy, maternal, and neonatal outcomes in women with osteogenesis imperfecta STUDY DESIGN: This is a cross-sectional, survey-based study. Appropriate participants of the Brittle Bone Disorders Consortium Contact Registry were invited to participate in the study. Self-reported information regarding pregnancy characteristics and maternal and neonatal outcomes was compared to the general population, referenced by literature-based standards, and comparisons between cohorts of women and fetuses with osteogenesis imperfecta were evaluated to determine if the presence of osteogenesis imperfecta conveyed an increase in antepartum, intrapartum, and postpartum complications and an increase in adverse neonatal outcomes when compared to the general population.

Results: 132 Participants completed the survey. Compared to the general population, women with osteogenesis imperfecta had higher rates of diabetes in pregnancy (13.3% vs. 7%, p=0.049, CI: 7.0%-19.6%), cesarean section (68.5% vs. 32.7%, p<0.001, CI: 59.9-77.1%), need for blood transfusion (8.3% vs. 1.5%, p=0.019, CI: 3.9-12.8%), and antepartum and postpartum fractures (RR 221, 95% CI: 59.3-823, p<0.001). Maternal hospitalization and cesarean rates were higher in individuals with moderate or severe osteogenesis imperfecta as compared to the women who reported mild osteogenesis imperfecta. Neonates born to women with osteogenesis imperfecta had higher risk for being low (26.2% vs. 6.8%, p<0.001) or very low birth weight (13.8% vs. 1.4%, p<0.001) infants as compared to the general population. Neonates born to women with osteogenesis imperfecta had a higher rate of neonatal intensive care unit admissions (19% vs. 5.68%, p<0.001) and higher neonatal mortality at 28 days of life (4.8% vs. 0.4%, p=0.026), regardless of neonatal osteogenesis imperfecta status.

Conclusion: Pregnancies for women with osteogenesis imperfecta are at an increased risk for complications including hemorrhage, fractures, diabetes, and increased neonatal morbidity.
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http://dx.doi.org/10.1016/j.ajogmf.2021.100362DOI Listing
March 2021

An Age-Related Exponential Decline in the Risk of Multiple Islet Autoantibody Seroconversion During Childhood.

Diabetes Care 2021 Feb 24. Epub 2021 Feb 24.

National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD.

Objective: Islet autoimmunity develops before clinical type 1 diabetes and includes multiple and single autoantibody phenotypes. The objective was to determine age-related risks of islet autoantibodies that reflect etiology and improve screening for presymptomatic type 1 diabetes.

Research Design And Methods: The Environmental Determinants of Diabetes in the Young study prospectively monitored 8,556 genetically at-risk children at 3- to 6-month intervals from birth for the development of islet autoantibodies and type 1 diabetes. The age-related change in the risk of developing islet autoantibodies was determined using landmark and regression models.

Results: The 5-year risk of developing multiple islet autoantibodies was 4.3% (95% CI 3.8-4.7) at 7.5 months of age and declined to 1.1% (95% CI 0.8-1.3) at a landmark age of 6.25 years ( < 0.0001). Risk decline was slight or absent in single insulin and GAD autoantibody phenotypes. The influence of sex, , and other susceptibility genes on risk subsided with increasing age and was abrogated by age 6 years. Highest sensitivity and positive predictive value of multiple islet autoantibody phenotypes for type 1 diabetes was achieved by autoantibody screening at 2 years and again at 5-7 years of age.

Conclusions: The risk of developing islet autoimmunity declines exponentially with age, and the influence of major genetic factors on this risk is limited to the first few years of life.
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http://dx.doi.org/10.2337/dc20-2122DOI Listing
February 2021

Children's erythrocyte fatty acids are associated with the risk of islet autoimmunity.

Sci Rep 2021 Feb 11;11(1):3627. Epub 2021 Feb 11.

Health and Well-Being Promotion Unit, Public Health and Welfare Department, Finnish Institute for Health and Welfare, P.O. Box 30, 00271, Helsinki, Finland.

Our aim was to investigate the associations between erythrocyte fatty acids and the risk of islet autoimmunity in children. The Environmental Determinants of Diabetes in the Young Study (TEDDY) is a longitudinal cohort study of children at high genetic risk for type 1 diabetes (n = 8676) born between 2004 and 2010 in the U.S., Finland, Sweden, and Germany. A nested case-control design comprised 398 cases with islet autoimmunity and 1178 sero-negative controls matched for clinical site, family history, and gender. Fatty acids composition was measured in erythrocytes collected at the age of 3, 6, and 12 months and then annually up to 6 years of age. Conditional logistic regression models were adjusted for HLA risk genotype, ancestry, and weight z-score. Higher eicosapentaenoic and docosapentaenoic acid (n - 3 polyunsaturated fatty acids) levels during infancy and conjugated linoleic acid after infancy were associated with a lower risk of islet autoimmunity. Furthermore, higher levels of some even-chain saturated (SFA) and monounsaturated fatty acids (MUFA) were associated with increased risk. Fatty acid status in early life may signal the risk for islet autoimmunity, especially n - 3 fatty acids may be protective, while increased levels of some SFAs and MUFAs may precede islet autoimmunity.
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http://dx.doi.org/10.1038/s41598-021-82200-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878879PMC
February 2021

Serum fatty acids and risk of developing islet autoimmunity: A nested case-control study within the TRIGR birth cohort.

Pediatr Diabetes 2021 Jun 24;22(4):577-585. Epub 2021 Feb 24.

Unit of Health Sciences, Faculty of Social Sciences, Tampere University, Tampere, Finland.

Background: Circulating fatty acids have been linked to development of type 1 diabetes.

Objectives: To study the prospective associations of serum fatty acids with the risk of islet autoimmunity in high-risk children.

Methods: A nested case-control selection was carried out within the TRIGR cohort, which included infants with HLA (DQB1 or DQA1)-conferred disease susceptibility and a first-degree relative with type 1 diabetes, born between 2002 and 2007 in 15 countries and followed-up until 2017. The present study included 244 case children positive for at least two islet autoantibodies (ICA, IAA, GADA, and IA-2A) and two control children were matched for country and age. Proportions of 26 serum fatty acids at cord blood and at 6, 12, and 18 months of age were assessed using gas-chromatography.

Results: The average proportions of the following fatty acids were associated with an increased risk of islet autoimmunity, adjusted for sex, HLA risk, and maternal type 1 diabetes: pentadecanoic acid (15:0) (OR 3.41: 95% CI 1.70, 6.85), heptadecanoic acid (iso 17:0) (2.64: 1.62, 4.28) and (anteiso 17:0) (2.27: 1.39, 3.70), stearic acid (18:0) (23.8: 2.32, 244.6), and conjugated linoleic acid (18:2n-7) (2.60: 1.47, 4.59). Breastfeeding and not having maternal type 1 diabetes were positively associated with levels of the above-mentioned fatty acids. N-3 fatty acids were not consistently associated with islet autoimmunity.

Conclusions: We found direct associations of pentadecanoic acid, heptadecanoic acid, stearic acid, and conjugated linoleic acid with the risk of islet autoimmunity. Further studies are needed to understand the complex role of fatty acids in the development of type 1 diabetes.
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http://dx.doi.org/10.1111/pedi.13189DOI Listing
June 2021

Growth and development of islet autoimmunity and type 1 diabetes in children genetically at risk.

Diabetologia 2021 Apr 21;64(4):826-835. Epub 2021 Jan 21.

Pediatrics Epidemiology Center, University of South Florida, Tampa, FL, USA.

Aims/hypothesis: We aimed to evaluate the relationship between childhood growth measures and risk of developing islet autoimmunity (IA) and type 1 diabetes in children with an affected first-degree relative and increased HLA-conferred risk. We hypothesised that being overweight or obese during childhood is associated with a greater risk of IA and type 1 diabetes.

Methods: Participants in a randomised infant feeding trial (N = 2149) were measured at 12 month intervals for weight and length/height and followed for IA (at least one positive out of insulin autoantibodies, islet antigen-2 autoantibody, GAD autoantibody and zinc transporter 8 autoantibody) and development of type 1 diabetes from birth to 10-14 years. In this secondary analysis, Cox proportional hazard regression models were adjusted for birthweight and length z score, sex, HLA risk, maternal type 1 diabetes, mode of delivery and breastfeeding duration, and stratified by residence region (Australia, Canada, Northern Europe, Southern Europe, Central Europe and the USA). Longitudinal exposures were studied both by time-varying Cox proportional hazard regression and by joint modelling. Multiple testing was considered using family-wise error rate at 0.05.

Results: In the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) population, 305 (14.2%) developed IA and 172 (8%) developed type 1 diabetes. The proportions of children overweight (including obese) and obese only were 28% and 9% at 10 years, respectively. Annual growth measures were not associated with IA, but being overweight at 2-10 years of life was associated with a twofold increase in the development of type 1 diabetes (HR 2.39; 95% CI 1.46, 3.92; p < 0.001 in time-varying Cox regression), and similarly with joint modelling.

Conclusions/interpretation: In children at genetic risk of type 1 diabetes, being overweight at 2-10 years of age is associated with increased risk of progression from multiple IA to type 1 diabetes and with development of type 1 diabetes, but not with development of IA. Future studies should assess the impact of weight management strategies on these outcomes.

Trial Registration: ClinicalTrials.gov NCT00179777.
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http://dx.doi.org/10.1007/s00125-020-05358-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940594PMC
April 2021

Effect of extensively hydrolyzed casein vs. conventional formula on the risk of asthma and allergies: The TRIGR randomized clinical trial.

Pediatr Allergy Immunol 2021 May 27;32(4):670-678. Epub 2021 Jan 27.

Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.

Background: The role of hydrolyzed infant formulas in the prevention of asthma and allergies remains inconsistent. We tested whether extensively hydrolyzed casein formula compared to conventional cow's milk-based formula prevented asthma, allergic rhinitis, or atopic eczema.

Methods: In the randomized double-blind Trial to Reduce IDDM in Genetically at Risk (TRIGR), comparing extensively hydrolyzed to standard cow's milk-based infant formula during the first 6-8 months of life, we assessed the effect of the intervention on the incidence of asthma, allergic rhinitis, and eczema when the children were 9- to 11-years old. The asthma, allergic rhinitis, and eczema occurrence was assessed using online standardized and validated ISAAC questionnaire. Of the 1106 children who participated in this Ancillary study, 560 had been randomized to the experimental (extensively hydrolyzed casein formula) and 546 to the control arm (cow's milk-based formula).

Results: The risk of persistent asthma, allergic rhinitis, or atopic eczema did not differ by treatment, the hazard ratios (95% CI) being 1.00 (0.66-1.52), 0.95 (0.66-1.38), and 0.89 (0.70-1.15), respectively, in the intention-to-treat analysis. Neither were there any differences in the per-protocol analysis.

Conclusions: Extensively hydrolyzed casein formula did not protect from asthma, rhinitis, or eczema in this population carrying genetic risk for type 1 diabetes.
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http://dx.doi.org/10.1111/pai.13452DOI Listing
May 2021

First-appearing islet autoantibodies for type 1 diabetes in young children: maternal life events during pregnancy and the child's genetic risk.

Diabetologia 2021 Mar 6;64(3):591-602. Epub 2021 Jan 6.

Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmo, Sweden.

Aims/hypothesis: Psychological stress has long been considered a possible trigger of type 1 diabetes, although prospective studies examining the link between psychological stress or life events during pregnancy and the child's type 1 diabetes risk are rare. The objective of this study was to examine the association between life events during pregnancy and first-appearing islet autoantibodies (IA) in young children, conditioned by the child's type 1 diabetes-related genetic risk.

Methods: The IA status of 7317 genetically at-risk The Environmental Determinants of Diabetes in the Young (TEDDY) participants was assessed every 3 months from 3 months to 4 years, and bi-annually thereafter. Reports of major life events during pregnancy were collected at study inception when the child was 3 months of age and placed into one of six categories. Life events during pregnancy were examined for association with first-appearing insulin (IAA) (N = 222) or GAD (GADA) (N = 209) autoantibodies in the child until 6 years of age using proportional hazard models. Relative excess risk due to interaction (RERI) by the child's HLA-DR and SNP profile was estimated.

Results: Overall, 65% of mothers reported a life event during pregnancy; disease/injury (25%), serious interpersonal (28%) and job-related (25%) life events were most common. The association of life events during pregnancy differed between IAA and GADA as the first-appearing autoantibody. Serious interpersonal life events correlated with increased risk of GADA-first only in HLA-DR3 children with the BACH2-T allele (HR 2.28, p < 0.0001), an additive interaction (RERI 1.87, p = 0.0004). Job-related life events were also associated with increased risk of GADA-first among HLA-DR3/4 children (HR 1.53, p = 0.04) independent of serious interpersonal life events (HR 1.90, p = 0.002), an additive interaction (RERI 1.19, p = 0.004). Job-related life events correlated with reduced risk of IAA-first (HR 0.55, p = 0.004), particularly in children with the BTNL2-GG allele (HR 0.48; 95% CI 0.31, 0.76).

Conclusions/interpretation: Specific life events during pregnancy are differentially related to IAA vs GADA as first-appearing IA and interact with different HLA and non-HLA genetic factors, supporting the concept of different endotypes underlying type 1 diabetes. However, the mechanisms underlying these associations remain to be discovered. Life events may be markers for other yet-to-be-identified factors important to the development of first-appearing IA.
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http://dx.doi.org/10.1007/s00125-020-05344-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880544PMC
March 2021

Validation of self-reported diagnosis of eosinophilic gastrointestinal disorders patients enrolled in the CEGIR contact registry.

Clin Res Hepatol Gastroenterol 2020 Nov 5:101555. Epub 2020 Nov 5.

Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.

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http://dx.doi.org/10.1016/j.clinre.2020.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108388PMC
November 2020

Plasma Metabolome and Circulating Vitamins Stratified Onset Age of an Initial Islet Autoantibody and Progression to Type 1 Diabetes: The TEDDY Study.

Diabetes 2021 01 26;70(1):282-292. Epub 2020 Oct 26.

Health Informatics Institute, University of South Florida, Tampa, FL.

Children's plasma metabolome, especially lipidome, reflects gene regulation and dietary exposures, heralding the development of islet autoantibodies (IA) and type 1 diabetes (T1D). The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 newborns by screening of HLA-DR-DQ genotypes at six clinical centers in four countries, profiled metabolome, and measured concentrations of ascorbic acid, 25-hydroxyvitamin D [25(OH)D], and erythrocyte membrane fatty acids following birth until IA seroconversion under a nested case-control design. We grouped children having an initial autoantibody only against insulin (IAA-first) or GAD (GADA-first) by unsupervised clustering of temporal lipidome, identifying a subgroup of children having early onset of each initial autoantibody, i.e., IAA-first by 12 months and GADA-first by 21 months, consistent with population-wide early seroconversion age. Differential analysis showed that infants having reduced plasma ascorbic acid and cholesterol experienced IAA-first earlier, while early onset of GADA-first was preceded by reduced sphingomyelins at infancy. Plasma 25(OH)D prior to either autoantibody was lower in T1D progressors compared with nonprogressors, with simultaneous lower diglycerides, lysophosphatidylcholines, triglycerides, and alanine before GADA-first. Plasma ascorbic acid and 25(OH)D at infancy were lower in HLA-DR3/DR4 children among IA case subjects but not in matched control subjects, implying gene expression dysregulation of circulating vitamins as latent signals for IA or T1D progression.
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http://dx.doi.org/10.2337/db20-0696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876562PMC
January 2021

Factors Associated With the Decline of C-Peptide in a Cohort of Young Children Diagnosed With Type 1 Diabetes.

J Clin Endocrinol Metab 2021 Mar;106(3):e1380-e1388

Department of Clinical Sciences, Lund University CRC, Skåne University Hospital, Malmö, Sweden.

Context: Understanding factors involved in the rate of C-peptide decline is needed to tailor therapies for type 1 diabetes (T1D).

Objective: Evaluate factors associated with rate of C-peptide decline after a T1D diagnosis in young children.

Design: Observational study.

Setting: Academic centers.

Participants: A total of 57 participants from the Environmental Determinants of Diabetes in the Young (TEDDY) study who were enrolled at 3 months of age and followed until T1D, and 56 age-matched children diagnosed with T1D in the community.

Intervention: A mixed meal tolerance test was used to measure the area under the curve (AUC) C-peptide at 1, 3, 6, 12, and 24 months postdiagnosis.

Outcome: Factors associated with rate of C-peptide decline during the first 2 years postdiagnosis were evaluated using mixed effects models, adjusting for age at diagnosis and baseline C-peptide.

Results: Adjusted slopes of AUC C-peptide decline did not differ between TEDDY subjects and community controls (P = 0.21), although the former had higher C-peptide baseline levels. In univariate analyses combining both groups (n = 113), younger age, higher weight and body mass index z-scores, female sex, an increased number increased number of islet autoantibodies, and IA-2A or ZnT8A positivity at baseline were associated with a higher rate of C-peptide loss. Younger age, female sex, and higher weight z-score remained significant in multivariate analysis (all P < 0.02). At 3 months after diagnosis, higher HbA1c became an additional independent factor associated with a higher rate of C-peptide decline (P < 0.01).

Conclusion: Younger age at diagnosis, female sex, higher weight z-score, and HbA1c were associated with a higher rate of C-peptide decline after T1D diagnosis in young children.
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http://dx.doi.org/10.1210/clinem/dgaa715DOI Listing
March 2021

Comparing Beta Cell Preservation Across Clinical Trials in Recent-Onset Type 1 Diabetes.

Diabetes Technol Ther 2020 12 20;22(12):948-953. Epub 2020 Oct 20.

Division of Pediatric Endocrinology, University of Florida, Gainesville, Florida, USA.

Several immunotherapies have demonstrated endogenous insulin preservation in recent-onset type 1 diabetes (T1D). We considered the primary results of rituximab, abatacept, teplizumab, alefacept, high-dose antithymocyte globulin (ATG), low-dose ATG, and low-dose ATG ± granulocyte-colony-stimulating factor trials in an attempt to rank the effectiveness of the agents studied. C-peptide 2-h area under the curve means were modeled using analysis of covariance. The experimental treatment group effect for each study, compared with its internal control, was estimated after adjusting for baseline C-peptide and age. Percentage increase in C-peptide over placebo and the absolute difference within study were calculated to compare and contrast effect size among interventions. Low-dose ATG (55% and 103%) and teplizumab (48% and 63%) ranked highest in C-peptide preservation at 1 and 2 years, respectively. Low-dose ATG and teplizumab show the greatest impact on C-peptide preservation among recent new-onset T1D studies; these should be further explored as core immunotherapies in the T1D prevention setting.
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http://dx.doi.org/10.1089/dia.2020.0305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757538PMC
December 2020

A combined risk score enhances prediction of type 1 diabetes among susceptible children.

Nat Med 2020 08 7;26(8):1247-1255. Epub 2020 Aug 7.

Pacific Northwest Research Institute, Seattle, WA, USA.

Type 1 diabetes (T1D)-an autoimmune disease that destroys the pancreatic islets, resulting in insulin deficiency-often begins early in life when islet autoantibody appearance signals high risk. However, clinical diabetes can follow in weeks or only after decades, and is very difficult to predict. Ketoacidosis at onset remains common and is most severe in the very young, in whom it can be life threatening and difficult to treat. Autoantibody surveillance programs effectively prevent most ketoacidosis but require frequent evaluations whose expense limits public health adoption. Prevention therapies applied before onset, when greater islet mass remains, have rarely been feasible because individuals at greatest risk of impending T1D are difficult to identify. To remedy this, we sought accurate, cost-effective estimation of future T1D risk by developing a combined risk score incorporating both fixed and variable factors (genetic, clinical and immunological) in 7,798 high-risk children followed closely from birth for 9.3 years. Compared with autoantibodies alone, the combined model dramatically improves T1D prediction at ≥2 years of age over horizons up to 8 years of age (area under the receiver operating characteristic curve ≥ 0.9), doubles the estimated efficiency of population-based newborn screening to prevent ketoacidosis, and enables individualized risk estimates for better prevention trial selection.
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http://dx.doi.org/10.1038/s41591-020-0930-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556983PMC
August 2020

A quantitative measure of treatment response in recent-onset type 1 diabetes.

Endocrinol Diabetes Metab 2020 Jul 14;3(3):e00143. Epub 2020 May 14.

Health Informatics Institute University of South Florida Tampa FL USA.

Introduction: This paper develops a methodology and defines a measure that can be used to separate subjects that received an experimental therapy into those that benefitted from those that did not in recent-onset type 1 diabetes. Benefit means a slowing (or arresting) the decline in beta-cell function over time. The measure can be applied to comparing treatment arms from a clinical trial or to response at the individual level.

Methods: An analysis of covariance model was fitted to the 12-month area under the curve C-peptide following a 2-hour mixed meal tolerance test from 492 individuals enrolled on five TrialNet studies of recent-onset type 1 diabetes. Significant predictors in the model were age and C-peptide at study entry. The observed minus the model-based expected C-peptide value (quantitative response, QR) is defined to reflect the effect of the therapy.

Results: A comparison of the primary hypothesis test for each study included and a t test of the QR value by treatment group were comparable. The results were also confirmed for a new TrialNet study, independent of the set of studies used to derive the model. With our proposed analytical method and using QR as the end-point, we conducted simulation studies, to estimate statistical power in detecting a biomarker that expresses differential treatment effect. The QR in its continuous form provided the greatest statistical power when compared to several ways of defining responder/non-responder using various QR thresholds.

Conclusions: This paper illustrates the use of the QR, as a measure of the magnitude of treatment effect at the aggregate and subject-level. We show that the QR distribution by treatment group provides a better sense of the treatment effect than simply giving the mean estimates. Using the QR in its continuous form is shown to have higher statistical power in comparison with dichotomized categorization.
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http://dx.doi.org/10.1002/edm2.143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375065PMC
July 2020

Hierarchical Order of Distinct Autoantibody Spreading and Progression to Type 1 Diabetes in the TEDDY Study.

Diabetes Care 2020 09 8;43(9):2066-2073. Epub 2020 Jul 8.

Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL.

Objective: The first-appearing β-cell autoantibody has been shown to influence risk of type 1 diabetes (T1D). Here, we assessed the risk of autoantibody spreading to the second-appearing autoantibody and further progression to clinical disease in The Environmental Determinants of Diabetes in the Young (TEDDY) study.

Research Design And Methods: Eligible children with increased HLA-DR-DQ genetic risk for T1D were followed quarterly from age 3 months up to 15 years for development of a single first-appearing autoantibody (GAD antibody [GADA], insulin autoantibody [IAA], or insulinoma antigen-2 autoantibody [IA-2A]) and subsequent development of a single second-appearing autoantibody and progression to T1D. Autoantibody positivity was defined as positivity for a specific autoantibody at two consecutive visits confirmed in two laboratories. Zinc transporter 8 autoantibody (ZnT8A) was measured in children who developed another autoantibody.

Results: There were 608 children who developed a single first-appearing autoantibody (IAA, = 282, or GADA, = 326) with a median follow-up of 12.5 years from birth. The risk of a second-appearing autoantibody was independent of GADA versus IAA as a first-appearing autoantibody (adjusted hazard ratio [HR] 1.12; 95% CI 0.88-1.42; = 0.36). Second-appearing GADA, IAA, IA-2A, or ZnT8A conferred an increased risk of T1D compared with children who remained positive for a single autoantibody, e.g., IAA or GADA second (adjusted HR 6.44; 95% CI 3.78-10.98), IA-2A second (adjusted HR 16.33; 95% CI 9.10-29.29; < 0.0001), or ZnT8A second (adjusted HR 5.35; 95% CI 2.61-10.95; < 0.0001). In children who developed a distinct second autoantibody, IA-2A (adjusted HR 3.08; 95% CI 2.04-4.65; < 0.0001) conferred a greater risk of progression to T1D as compared with GADA or IAA. Additionally, both a younger initial age at seroconversion and shorter time to the development of the second-appearing autoantibody increased the risk for T1D.

Conclusions: The hierarchical order of distinct autoantibody spreading was independent of the first-appearing autoantibody type and was age-dependent and augmented the risk of progression to T1D.
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http://dx.doi.org/10.2337/dc19-2547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440899PMC
September 2020

Association of diabetes-related autoantibodies with the incidence of asthma, eczema and allergic rhinitis in the TRIGR randomised clinical trial.

Diabetologia 2020 09 17;63(9):1796-1807. Epub 2020 Jun 17.

Unit of Public Health Promotion, National Institute for Health and Welfare, Helsinki, Finland.

Aims/hypothesis: This paper presents the relationship between islet autoantibodies, precursors of type 1 diabetes, and the development of persistent asthma, allergic rhinitis and atopic eczema.

Methods: A total of 2159 newborns who had a first-degree relative with type 1 diabetes and selected HLA genotypes were followed until the youngest participant reached 10 years of age. Islet cell antibodies (ICA) were detected using indirect immunofluorescence. Autoantibodies to insulin (IAA), GAD (GADA), the tyrosine phosphatase-related insulinoma-associated 2 molecule (IA-2A) and zinc transporter 8 (ZnT8A) were quantified with the use of specific radiobinding assays. As an ancillary study, the incidence of asthma, allergic rhinitis and eczema was assessed in 1106 of these children using the International Study of Asthma and Allergies in Childhood (ISAAC) core questionnaire when the children were 9-11 years old. HRs with 95% CIs were calculated to depict the incidence of these diseases following seroconversion to autoantibody positivity.

Results: The cumulative incidence of atopic eczema, allergic rhinitis and persistent asthma were 22%, 9% and 7.5%, respectively, by 9-11 years of age. The occurrence of diabetes-related autoantibodies showed a protective association with subsequently reported incidence of asthma and eczema. The incidence of rhinitis was not significantly related to the occurrence of IAA or GADA (statistical power was limited), but demonstrated the same inverse relationship as did the other diseases with ICA or when multiple autoantibodies first appeared together.

Conclusions/interpretation: The findings add evidence to the relationships between these atopic diseases and diabetes-related autoimmunity and also suggest that, for eczema, the interaction depends upon which autoantibody appeared first.

Trial Registration: ClinicalTrials.gov NCT00179777 Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05188-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416479PMC
September 2020

High Patient Disease Burden in a Cross-sectional, Multicenter Contact Registry Study of Eosinophilic Gastrointestinal Diseases.

J Pediatr Gastroenterol Nutr 2020 10;71(4):524-529

Department of Pediatrics, Cincinnati Children's Hospital Medical Center.

Objectives: Clinical features of eosinophilic esophagitis (EoE) have been well-described in the literature, however, characterization of features experienced by patients with other eosinophilic gastrointestinal diseases (EGIDs) is lacking. Using data collected from a patient contact registry, we sought to characterize and contrast patient-reported gastrointestinal and extragastrointestinal symptoms and comorbidities in non-EoE EGIDs, including eosinophilic gastritis, gastroenteritis and colitis, relative to EoE.

Methods: We conducted a cross-sectional study of contact registry data collected from 2015 to 2018. Statistical comparisons were made using chi-square (categorical measures) and the Mann-Whitney U test (continuous measures). Multivariable analyses were used to evaluate associations between treatment and feelings of isolation.

Results: Of the 715 reporting an EGID diagnosis (n = 525 EoE; n = 190 non-EoE EGID), a higher proportion of those with a non-EoE EGID reported more frequent specific and nonspecific gastrointestinal symptoms, including nausea, abdominal pain, diarrhea, constipation, and bloating (P < 0.01 for all). Participants with a non-EoE EGID were more likely to report higher frequency of fatigue, isolation, and deep muscle or joint pain (P < 0.01 for all). Specific food elimination and elemental formula treatments were associated with increased odds of more frequent (at least weekly) feelings of isolation for participants with EoE (adjusted odds rtaio [aOR]: 2.4; 95% confidence interval [CI]: 1.5--4.1 for specific food elimination and adjusted OR: 1.9; 95% CI: 1.2--3.3 for elemental formula).

Conclusions: Significant differences exist in the symptoms and comorbidities experienced between those with EoE versus non-EoE EGIDs. Additional investigation is needed to elucidate the factors that may contribute to the high disease burden of these poorly understood conditions.
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http://dx.doi.org/10.1097/MPG.0000000000002817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574400PMC
October 2020

Protocol for a randomized multicenter study for isolated skin vasculitis (ARAMIS) comparing the efficacy of three drugs: azathioprine, colchicine, and dapsone.

Trials 2020 Apr 28;21(1):362. Epub 2020 Apr 28.

Divison of Rheumatology and Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.

Background: Skin-limited forms of vasculitis, while lacking systemic manifestations, can persist or recur indefinitely, cause pain, itch, or ulceration, and be complicated by infection or scarring. High-quality evidence on how to treat these conditions is lacking. The aim of this comparative effectiveness study is to determine the optimal management of patients with chronic skin-limited vasculitis.

Methods: ARAMIS is a multicenter, sequential, multiple assignment randomized trial with an enrichment design (SMARTER) aimed at comparing the efficacy of three drugs-azathioprine, colchicine, and dapsone-commonly used to treat various forms of isolated skin vasculitis. ARAMIS will enroll patients with isolated cutaneous small or medium vessel vasculitis, including cutaneous small vessel vasculitis, immunoglobulin A (IgA) vasculitis (skin-limited Henoch-Schönlein purpura), and cutaneous polyarteritis nodosa. Patients not responding to the initial assigned therapy will be re-randomized to one of the remaining two study drugs (Stage 2). Those with intolerance or contraindication to a study drug can be randomized directly into Stage 2. Target enrollment is 90 participants, recruited from international centers affiliated with the Vasculitis Clinical Research Consortium. The number of patients enrolled directly into Stage 2 of the study will be capped at 10% of the total recruitment target. The primary study endpoint is the proportion of participants from the pooled study stages with a response to therapy at month 6, according to the study definition.

Discussion: ARAMIS will help identify effective agents for skin-limited forms of vasculitis, an understudied group of diseases. The SMARTER design may serve as an example for future trials in rare diseases.

Trial Registration: ClinicalTrials.gov: NCT02939573. Registered on 18 October 2016.
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http://dx.doi.org/10.1186/s13063-020-04285-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189702PMC
April 2020

A novel approach to conducting clinical trials in the community setting: utilizing patient-driven platforms and social media to drive web-based patient recruitment.

BMC Med Res Methodol 2020 03 13;20(1):58. Epub 2020 Mar 13.

Health Informatics Institute, University of South Florida, 3650 Spectrum Blvd., Suite 100, Tampa, FL, 33612, USA.

Background: Participant recruitment for clinical research studies remains a significant challenge for researchers. Novel approaches to recruitment are necessary to ensure that populations are easier to reach. In the context of rare diseases, social media provides a unique opportunity for connecting with patient groups that have representatively lower diagnosis rates when compared with more common diseases or illness. We describe the implementation of designing a patient-centered approach to message design for the purposes of recruiting patients for clinical research studies for rare disease populations.

Methods: Using an iterative research approach, we analyzed our previous experience of using web-based direct-to-patient recruitment methods to compare these online strategies with traditional center of excellence recruitment strategies. After choosing six research studies for inclusion in the previous study, in-depth, online interviews (n = 37) were conducted with patients represented in each disease category to develop and test recruitment message strategies for social media and a Web-based platform for patients to access study information and pre-screen. Finally, relationships were established with Patient Advocacy Groups representing each rare disease category to ensure further dissemination of recruitment materials via their own social media networks.

Results: Guided by social marketing theory, we created and tested various recruitment message designs. Three key message concepts preferred by patients emerged: (1) infographic; (2) positive emotional messages; and (3) educational information for sharing. A base study website was designed and created based on data from patient interviews. This website includes the option for potential participants to pre-screen and determine their eligibility for the study.

Conclusions: Study participants report wanting to be involved in the design and implementation of recruitment approaches for clinical research studies. The application of the aforementioned methods could aide in the evolution of clinical research practices for the recruitment of both rare and common diseases, where patient-centric approaches can help to create targeted messages designs that participants pre-test and support.
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http://dx.doi.org/10.1186/s12874-020-00926-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069058PMC
March 2020

Longitudinal Metabolome-Wide Signals Prior to the Appearance of a First Islet Autoantibody in Children Participating in the TEDDY Study.

Diabetes 2020 03 6;69(3):465-476. Epub 2020 Feb 6.

Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL

Children at increased genetic risk for type 1 diabetes (T1D) after environmental exposures may develop pancreatic islet autoantibodies (IA) at a very young age. Metabolic profile changes over time may imply responses to exposures and signal development of the first IA. Our present research in The Environmental Determinants of Diabetes in the Young (TEDDY) study aimed to identify metabolome-wide signals preceding the first IA against GAD (GADA-first) or against insulin (IAA-first). We profiled metabolomes by mass spectrometry from children's plasma at 3-month intervals after birth until appearance of the first IA. A trajectory analysis discovered each first IA preceded by reduced amino acid proline and branched-chain amino acids (BCAAs), respectively. With independent time point analysis following birth, we discovered dehydroascorbic acid (DHAA) contributing to the risk of each first IA, and γ-aminobutyric acid (GABAs) associated with the first autoantibody against insulin (IAA-first). Methionine and alanine, compounds produced in BCAA metabolism and fatty acids, also preceded IA at different time points. Unsaturated triglycerides and phosphatidylethanolamines decreased in abundance before appearance of either autoantibody. Our findings suggest that IAA-first and GADA-first are heralded by different patterns of DHAA, GABA, multiple amino acids, and fatty acids, which may be important to primary prevention of T1D.
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http://dx.doi.org/10.2337/db19-0756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034190PMC
March 2020

Serum 25-hydroxyvitamin D concentration in childhood and risk of islet autoimmunity and type 1 diabetes: the TRIGR nested case-control ancillary study.

Diabetologia 2020 04 7;63(4):780-787. Epub 2020 Jan 7.

Department of Public Health Solutions, National Institute for Health and Welfare, PO Box 30, 00271, Helsinki, Finland.

Aims/hypothesis: Our aim was to study the association between serum 25-hydroxyvitamin D (25OHD) concentration and islet autoimmunity and type 1 diabetes in children with an increased genetic risk of type 1 diabetes.

Methods: Serum samples for 25OHD measurements were obtained in the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) ancillary study (Divia) from children in 15 countries. Case children (n = 244) were defined as having positivity for at least two out of four diabetes-associated autoantibodies measured at any one sample. For each case child, two control children were selected matched for country and date of birth (±1 year) (n = 488). Of the case children, 144 developed type 1 diabetes. Serum 25OHD was measured repeatedly in infancy and childhood and was compared according to age at the first seroconversion (at 6, 12 and 18 months prior to and at seroconversion) and calendar age (0, 6, 12 and 18 months).

Results: In children with islet autoimmunity, mean serum 25OHD concentration was lower 18 months prior to the age of first seroconversion of the case children compared with the control children (57.7 vs 64.8 nmol/l, p = 0.007). In children with type 1 diabetes (n = 144), mean serum 25OHD concentration was lower 18 months prior to the age of the first seroconversion (58.0 vs 65.0 nmol/l, p = 0.018) and at the calendar age of 12 months (70.1 vs 75.9 nmol/l, p = 0.031) than in their control counterparts. Analyses were adjusted for month of sample collection, human leucocyte antigen genotype, maternal type 1 diabetes and sex.

Conclusions/interpretation: The results suggest that early postnatal vitamin D may confer protection against the development of type 1 diabetes.

Trial Registration: ClinicalTrials.gov NCT00179777.
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http://dx.doi.org/10.1007/s00125-019-05077-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054378PMC
April 2020

Distinct Growth Phases in Early Life Associated With the Risk of Type 1 Diabetes: The TEDDY Study.

Diabetes Care 2020 03 2;43(3):556-562. Epub 2020 Jan 2.

Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL.

Objective: This study investigates two-phase growth patterns in early life and their association with development of islet autoimmunity (IA) and type 1 diabetes (T1D).

Research Design And Methods: The Environmental Determinants of Diabetes in the Young (TEDDY) study followed 7,522 genetically high-risk children in Sweden, Finland, Germany, and the U.S. from birth for a median of 9.0 years (interquartile range 5.7-10.6) with available growth data. Of these, 761 (10.1%) children developed IA and 290 (3.9%) children were diagnosed with T1D. Bayesian two-phase piecewise linear mixed models with a random change point were used to estimate children's individual growth trajectories. Cox proportional hazards models were used to assess the effects of associated growth parameters on the risks of IA and progression to T1D.

Results: A higher rate of weight gain in infancy was associated with increased IA risk (hazard ratio [HR] 1.09 [95% CI 1.02, 1.17] per 1 kg/year). A height growth pattern with a lower rate in infancy (HR 0.79 [95% CI 0.70, 0.90] per 1 cm/year), higher rate in early childhood (HR 1.48 [95% CI 1.22, 1.79] per 1 cm/year), and younger age at the phase transition (HR 0.76 [95% CI 0.58, 0.99] per 1 month) was associated with increased risk of progression from IA to T1D. A higher rate of weight gain in early childhood was associated with increased risk of progression from IA to T1D (HR 2.57 [95% CI 1.34, 4.91] per 1 kg/year) in children with first-appearing GAD autoantibody only.

Conclusions: Growth patterns in early life better clarify how specific growth phases are associated with the development of T1D.
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http://dx.doi.org/10.2337/dc19-1670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035588PMC
March 2020

Prospective virome analyses in young children at increased genetic risk for type 1 diabetes.

Nat Med 2019 12 2;25(12):1865-1872. Epub 2019 Dec 2.

Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA.

Viruses are implicated in autoimmune destruction of pancreatic islet β cells, which results in insulin deficiency and type 1 diabetes (T1D). Certain enteroviruses can infect β cells in vitro, have been detected in the pancreatic islets of patients with T1D and have shown an association with T1D in meta-analyses. However, establishing consistency in findings across studies has proven difficult. Obstacles to convincingly linking RNA viruses to islet autoimmunity may be attributed to rapid viral mutation rates, the cyclical periodicity of viruses and the selection of variants with altered pathogenicity and ability to spread in populations. β cells strongly express cell-surface coxsackie and adenovirus receptor (CXADR) genes, which can facilitate enterovirus infection. Studies of human pancreata and cultured islets have shown significant variation in enteroviral virulence to β cells between serotypes and within the same serotype. In this large-scale study of known eukaryotic DNA and RNA viruses in stools from children, we evaluated fecally shed viruses in relation to islet autoimmunity and T1D. This study showed that prolonged enterovirus B rather than independent, short-duration enterovirus B infections may be involved in the development of islet autoimmunity, but not T1D, in some young children. Furthermore, we found that fewer early-life human mastadenovirus C infections, as well as CXADR rs6517774, independently correlated with islet autoimmunity.
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http://dx.doi.org/10.1038/s41591-019-0667-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898786PMC
December 2019

Association Between Endoscopic and Histologic Findings in a Multicenter Retrospective Cohort of Patients with Non-esophageal Eosinophilic Gastrointestinal Disorders.

Dig Dis Sci 2020 07 26;65(7):2024-2035. Epub 2019 Nov 26.

Center for Esophageal Diseases and Swallowing and Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, CB #7080, Chapel Hill, NC, 27599, USA.

Background: Little is known about the endoscopic and histologic findings of non-esophageal eosinophilic gastrointestinal diseases (EGID).

Aim: To characterize the presenting endoscopic and histologic findings in patients with eosinophilic gastritis (EG), eosinophilic gastroenteritis (EGE), and eosinophilic colitis (EC) at diagnosis and 6 months after initiating the treatment.

Methods: We conducted a retrospective cohort study at 6 US centers associated with the Consortium of Eosinophilic Gastrointestinal Researchers. Data abstracted included demographics, endoscopic findings, tissue eosinophil counts, and associated histologic findings at diagnosis and, when available, after initial treatment.

Results: Of 373 subjects (317 children and 56 adults), 142 had EG, 123 EGE, and 108 EC. Normal endoscopic appearance was the most common finding across all EGIDs (62% of subjects). Baseline tissue eosinophil counts were quantified in 105 (74%) EG, 36 (29%) EGE, and 80 (74%) EC subjects. The mean peak gastric eosinophil count across all sites was 87 eos/hpf for EG and 78 eos/hpf for EGE. The mean peak colonic eosinophil count for EC subjects was 76 eos/hpf (range 10-500). Of the 29% of subjects with post-treatment follow-up, most had an improvement in clinical, endoscopic, and histologic findings regardless of treatment utilized. Reductions in tissue eosinophilia correlated with improvements in clinical symptoms as well as endoscopic and histologic findings.

Conclusions: In this large cohort, normal appearance was the most common endoscopic finding, emphasizing the importance of biopsy, regardless of endoscopic appearance. Decreased tissue eosinophilia was associated with improvement in symptoms, endoscopic, and histologic findings, showing that disease activity is reversible.
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http://dx.doi.org/10.1007/s10620-019-05961-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315780PMC
July 2020

Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes.

Diabetes Care 2020 01 21;43(1):5-12. Epub 2019 Nov 21.

Department of Pediatrics, University of Florida, Gainesville, FL.

The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.
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http://dx.doi.org/10.2337/dc19-0880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925574PMC
January 2020

Metagenomics of the faecal virome indicate a cumulative effect of enterovirus and gluten amount on the risk of coeliac disease autoimmunity in genetically at risk children: the TEDDY study.

Gut 2020 08 19;69(8):1416-1422. Epub 2019 Nov 19.

The Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, Lund, Sweden.

Objective: Higher gluten intake, frequent gastrointestinal infections and adenovirus, enterovirus, rotavirus and reovirus have been proposed as environmental triggers for coeliac disease. However, it is not known whether an interaction exists between the ingested gluten amount and viral exposures in the development of coeliac disease. This study investigated whether distinct viral exposures alone or together with gluten increase the risk of coeliac disease autoimmunity (CDA) in genetically predisposed children.

Design: The Environmental Determinants of Diabetes in the Young study prospectively followed children carrying the HLA risk haplotypes DQ2 and/or DQ8 and constructed a nested case-control design. From this design, 83 CDA case-control pairs were identified. Median age of CDA was 31 months. Stool samples collected monthly up to the age of 2 years were analysed for virome composition by Illumina next-generation sequencing followed by comprehensive computational virus profiling.

Results: The cumulative number of stool enteroviral exposures between 1 and 2 years of age was associated with an increased risk for CDA. In addition, there was a significant interaction between cumulative stool enteroviral exposures and gluten consumption. The risk conferred by stool enteroviruses was increased in cases reporting higher gluten intake.

Conclusions: Frequent exposure to enterovirus between 1 and 2 years of age was associated with increased risk of CDA. The increased risk conferred by the interaction between enteroviruses and higher gluten intake indicate a cumulative effect of these factors in the development of CDA.
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http://dx.doi.org/10.1136/gutjnl-2019-319809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234892PMC
August 2020